Delivery device, method of using and method of manufacturing

ABSTRACT

An active principle delivery device ( 1 ) comprising an inner capsule ( 4 ) within an outer capsule ( 2 ), the inner and outer capsules ( 4,2 ) containing the same active principle ( 5,3 ), with at least the outer capsule ( 2 ) being a hard capsule and the active principle ( 3,5 ) in at least one of the capsules ( 2,4 ), comprising a fluid. Also provided is a method of fabricating such a delivery device ( 1 ), as well as a method of controlling the pharmaco-kinetic profile of an active principle.

CROSS REFERENCE TO RELATED APPLICATIONS

This application claims the benefit of International Application No.PCT/GB01/03247 filed Jul. 19, 2001, having a priority claim to Britishpatent application numbers GB 0017673.5 filed Jul. 20, 2000, and GB0028335.8 Filed Nov. 21, 2000.

BACKGROUND OF THE INVENTION

(1) Field of the Invention

This invention relates to a delivery device and a method of delivering asubstance to at least one location, more particularly the inventionrelates to a delivery device comprising one or more capsules within anouter capsule, with at least two of said capsules containing the sameactive principle and a method of delivering that active principle.

(2) Description of the Related Art

Capsule technology has been developing for over one hundred years and isnow at the stage where many medicaments are formulated so as to beencapsulated within a gelatin capsule. The benefits of such formulationsreside in the fact that the capsules are often easy for a patient orother consumer to swallow or use and the capsule can contain a largeamount of the particular medicament for delivery to the individual, theactual capsule dissolving in the stomach or other part of the intestinaltract.

Indeed, to ensure that a particular medicament is delivered to thedesired site, a large amount of research has been carried out in coatingtechniques. Such techniques are used to control or at least vary thetime or location of dissolution of the capsule and, consequently, thetime or location of release of the medicament.

Several known techniques have been developed for the administration ofmore than one active principle at a time or at short intervals whilstthe active principle is in tablet form. In those cases, coatings arealso used to vary or control the release time or location of that activeprinciple.

U.S. Pat. No. 1,815,902 (Ellzey) discloses a double capsule, with onecapsule within the other, for administering medicaments in which aninner hard gel capsule contains medicament, whilst an outer hard gelcapsule contains an innocuous alkaline material.

FR 1454013 (Pluripharm) relates to another type of double capsule withdifferent medicaments, in solid form, in the inner and outer capsuleswhich are made of hard gel, whilst DE 2729068 (Liedtke) is directed to adouble capsule in which the same or different active principles in solidform are provided in inner and outer hard gel capsules, with any liquidsbeing provided solely in inner and outer soft gel capsules.

In FR 2524311 (Azalbert), there is described another double capsule forthe ingestion of medicinal agents which are different and incompatiblewith one another. The inner and outer capsules are of hard gel, with themedicinal agents possibly being in liquid form.

EP 0116311 (Morishita Jintan Co et al) teaches a double soft gel capsulewith the inner and outer capsules containing different medicines, whilstEP 0130163 (Pharmacia) discloses a double capsule with the inner capsulecontaining an allergen and the outer capsule containing an antiallergiesubstance.

U.S. Pat. No. 5,310,555 (Zimmer) is directed to a method of deliveringincompatible and different compounds in vivo, with live intestinal orrumen microorganisms in an inner capsule and a nutritional supplement inan outer shell in which the inner capsule is contained.

EP 0624365 (ASTA Medica) describes a form of double capsule arrangementin which an outer sheath has bioadhesive properties and contains acapsule containing at least one hygroscopic substance and non-liquidactive agent tablets.

WO 95/10262 (RP Scherer Corporation) relates to a controlled releasedevice for delivering a liquid substance to a patient, wherein differentmaterials are contained in a double capsule. The liquid substance iscontained in an inner soft or hard gel capsule and an inert solidexcipient is contained in an outer hard gel capsule, with awater-swellable material in the outer capsule for causing disengagementof the capsules upon exposure to an aqueous medium.

WO 99/30693, AXCAN PHARMA shows that it is possible to provide a doublecapsule for the administration of active medicaments in multipletherapies. This disclosure considers the possibility of treating amicroorganism, such as Helicobacter pylori, with known solid medicamentsin a double capsule.

The multiple capsule delivery devices discussed above show that is knownto provide double, triple and, sometimes, quadruple therapies for thetreatment of many conditions, wherein the inner and outer capsules canbe provided in certain, but not all, combinations of solid and soft getcapsules containing the same or different active principles in solid orliquid form.

However, none of the prior art delivery devices discussed above everdiscloses, whether directly or by implication, the use of the sameactive principle as a fluid, such as liquid or semi-solid, in aparticular multiple capsule format for the treatment of a plurality ofconditions.

Also, these known multiple capsule delivery devices provide treatmentregimes which are limited, as it has been found to be difficult tocontrol and vary the posologies, particularly when solid activeprinciples are employed. Indeed, it is known also that certain activeprinciples are not amenable to patients in solid form and it is wellestablished that the most effective dose of most medicaments occurs whenthe active principles are in liquid form, for example, as an aqueoussolution, suspension, micelle or emulsion.

BRIEF SUMMARY OF THE INVENTION

Accordingly, it is an object of the invention to provide a deliverydevice which overcomes the problems associated with the known devices ofthe prior art discussed above. It is also an object to provide adelivery device which can be used in the treatment of a plurality ofconditions, where at least one desired form of active principle is fluidand where it is desired to control both the release rate and site ofrelease of the active principle.

Thus, a first aspect of the invention provides an active principledelivery device comprising an inner capsule within an outer capsule,wherein:

the inner and outer capsules contain the same active principle;

at least the outer capsule is a hard capsule; and

the active principle in at least one of the capsules comprises a fluid(as hereinafter defined).

A second aspect of the invention resides in a method of fabricating anactive principle delivery device, comprising:

providing a first capsule and a second capsule of which at least thefirst capsule is a hard capsule;

placing the same active principle in each of the first and secondcapsules, with the active principle in at least one of the capsulescomprising a fluid (as hereinafter defined); and

placing the second, active principle-containing, capsule within thefirst, active principle-containing, hard capsule.

In a third aspect of the invention, there is provided a method ofcontrolling the pharmaco-kinetic profile of an active principlecomprising:

determining the most efficacious site of active principle release;

placing an active principle in a first hard capsule;

placing the same active principle in a second capsule within the activeprinciple-containing, first hard capsule, with the active principle inat least one of the first and second capsules comprising a fluid (ashereinafter defined), to provide a delivery device;

delivering the delivery device to the predetermined active principlerelease site; and

controlling the release of the active principle at the site.

In preferred embodiment to be described hereinbelow, the activeprinciple is medicinal and/or nutritional.

Throughout this specification, the term “fluid” or derivatives thereofis used to describe a material which is a liquid or a semi-solid but nota gas, a liquid being defined as a material which flows under ambientconditions without external influences, whilst a semi-solid is definedas a material or mixture of material which has a consistency that variesaccording to its conditions within an ambient range and which may havecharacteristics of both a liquid and a solid. Examples of semi-solidsinclude creams, pastes, ointments, suspensions, emulsions, thixotropeand waxes. Changes in ambient conditions, such as a temperature change,could alter a semi-solid to a more liquid state, whilst agitation, suchas shaking, could change a thixotrope from a more solid state to a moreliquid state.

At least a portion of the active principle may be a fluid either at orimmediately prior to its time of use or during its manufacture

Although the first, outer capsule is a hard capsule, the second, innercapsule may be a hard or soft capsule and each may be constructed from,for example, gelatin, plasticised gelatin, hydroxy propyl methylcellulose (HPMC), starch or agar. Each of the inner and outer capsulesmay be coated or uncoated. In a preferred embodiment, the second innercapsule is a hard capsule and the active principle in both the inner andouter capsules comprises a fluid.

Preferably, the fluid is a liquid which may be a solution or suspensionand may comprise suspended solids which may be a powder, pellet, orgranules and which may be coated or uncoated. The liquid may also bethermosoftening. At least one of the capsules may contain the sameactive principle in more than one phase, for example, liquid, semi-solidand/or solid phases.

DETAILED DESCRIPTION OF THE INVENTION

The delivery device may comprise more than one second, inner capsulewithin the first, outer capsule, the second, inner capsules beingarranged in parallel and/or in series.

In a preferred embodiment, the delivery device provides a pharmaceuticaldosage form for the administration of the same active principle insingle therapies.

Also, the device may comprise an activator or co-reactant for the activeprinciple.

BRIEF DESCRIPTION OF THE DRAWINGS

The various aspects of the invention will now be described by way ofexample only, and with reference to the accompanying drawings in which:

FIG. 1 is a section through a first embodiment of delivery device;

FIG. 2 is a section through a second embodiment of delivery device;

FIG. 3 is a section through a third embodiment of delivery device; and

FIGS. 4A to 4D are example representations of pharmaco-kinetic profiles.

Referring firstly to FIG. 1, a double capsule delivery device, indicatedgenerally at 1, comprises a first, outer hard capsule 2 containing aliquid active principle 3 and a second, inner hard capsule 4 which alsocontains the same liquid active principle 5 as that contained in theouter hard capsule 2 and may be coated, as shown at 6.

Similarly, FIG. 2 illustrates a triple capsule delivery device,indicated generally at 11, which comprises a first, outer hard capsule12 containing a liquid active principle 13 and a second, inner hardcapsule 14 which also contains the same liquid active principle 15 asthat contained in the outer hard capsule 12 and may be coated, as shownat 18. The second, inner hard capsule 14 also contains a third, innerhard capsule 16 which, in turn, contains the same active principle asthat contained in the first and second, outer and inner hard capsule 12and 14 but in solid particulate form. That second, inner hard capsule 14may also be coated, as shown at 19. The capsules 12, 14 and 16 are inseries with each other.

Referring now to FIG. 3, a multiple capsule delivery device, indicatedgenerally at 21, comprises a first, outer hard capsule 22 containing aliquid active principle 23 and four inner hard capsules 24 containing anactive principle 25 which is the same as that contained in the first,outer capsule 22 but in semi-solid form. The four inner capsules 24 arein parallel with each other but in series with the outer capsule 22.

Each capsule 2, 4; 12, 14, 16; 22, 24 may be filled using standardcapsule-filling technology, such as intermittent or continuous motioncapsule filling machines equipped with dosators, to place the sameactive principle therein. Similar technology may be used to place theinner capsules 4; 14, 16; 24 within the respective outer capsules 2, 12,22.

Although the first outer capsule 2, 12, 22 is a hard capsule, as are theinner capsules 4; 14, 16; 24 in the three embodiments described above,the inner capsules 4; 14, 16; 24 may be soft capsules. However, anycombination of hard and soft inner capsules may be employed. Also,although the first, outer hard capsule 2, 12, 22 of those threeembodiments contains the active principle as a liquid, it need notnecessarily, as long as at least one of the outer capsules 2, 12, 22 andthe inner capsules 4; 14, 16; 24 contains the active principle as aliquid.

The outer hard capsule 2, 12, 22 may be made from any suitable materialwhich will depend upon application requirements. Such materials mayinclude hard gelatin, hydroxy propyl methyl cellulose (HPMC) and starch,whilst any inner capsule 4; 14, 16; 24 which is hard may be made fromsuch a material. Alternatively, and if any inner capsule is a softcapsule, then such may be made from soft gelatin or agar.

It is well established in the medical treatment of ailments, inparticular, human ailments, that there are two important thresholds fordrugs. The first threshold is the therapeutic threshold, which may bedefined as the concentration of active principle at which the principleshows a therapeutic effect on the particular ailment. The second suchthreshold is the toxic threshold, which occurs when the amount of drugreaches a concentration at which the person who has ingested the drugis, or at least starts to become, poisoned thereby. This effectiveconcentration range between the therapeutic and toxic thresholds may bedefined as the activity window.

Active principles, once released, are normally absorbed by the bodywhere they are either metabolised or excreted. Obviously, the balancebetween release/absorbance rate and removal rate (for example, the sumof the rates of excretion and metabolisation) provides the so-calledpharmaco-kinetic profile of a particular active principle. Thepharmaco-kinetic profile for a particular active principle may benon-ideal. For example, the concentration of active principle at thedesired site may rapidly fall below its therapeutic threshold oncereleased. Alternatively, and as is more usual, the concentration of thedrug may slowly reduce to below the therapeutic threshold beforesufficient time has elapsed for the active principle to yield thedesired result.

A solution to this low active principle concentration problem is simplyto administer more of the active principle. However, whilst this mayincrease the concentration of the active principle and concomitantly thetime that the patient's blood contains above the therapeutic threshold,it may also increase the concentration above the toxic threshold,consequently poisoning the person to whom the drug was administered.Indeed, some active principles have very small activity windows andtherefore administering large doses of the active principle isundesirable. In such cases, it is usual to prescribe complicatedadministration regimes wherein a patient is forced to take a largenumber of relatively small dose drugs frequently. Such regimes arecostly and difficult to administer, act to limit or control thepatient's freedoms and, moreover, may be difficult to ensure patient'scompliance therewith.

With regard now to FIG. 4A, there is shown a pharmaco-kinetic profile Wof active principle concentration against time for a particular activeprinciple. The curve W is found after administration of an activeprinciple, in a single therapy, in the form of the delivery device 1,shown in FIG. 1.

The delivery device 1 comprises the outer hard capsule 2 which containsthe liquid active principle 3 and which is uncoated and the innercapsule 4 which also contains the same liquid active principle 5 andwhich is provided with an enteric or erodible coating 6. Once ingested,represented by R₁, the outer capsule 2 is quickly broken down and thecontents 3 made available, showing an increase in the concentration ofthe active principle. The coating 6 on the inner capsule 4 preventsimmediate release of the contents 5 thereof. However, over time thecoating breaks down and, at R₂, the contents 5 are released andtherefore made available to the body. The effect, as shown in FIG. 4A,is a superposition of two active principle concentration curves toprovide the composite pharmaco-kinetic profile W shown.

In FIG. 4A, the active principle 3, 5 has a relatively long absorptionhalf-life, which is to say that it is slowly absorbed by the body. Incontrast, FIG. 4B shows a situation wherein the active principle 3, 5has a short absorption half-life and is rapidly absorbed (andeliminated) by the body. A delivery device 1, such as that shown in FIG.1, may be used and again, the inner capsule 4 is coated at 6 to preventearly release of the active principle 5 contained therein. As can beseen in FIG. 4B, the superposition of the two active principleconcentration curves provides a composite pharmaco-kinetic profile Xshowing the pulsed release of the principle 3, 5. The activity window AWof the same principle 3, 5 is also indicated (AW=toxic threshold(To)−therapeutic threshold (Th)). Such a formulation, as is containedwithin the delivery device 1, allows for continual administration of anefficacious dose whilst the patient only has to take a single capsule.

Obviously, a delivery device 11 such as that shown in FIG. 2 could alsobe configured to provide pulsed release of a principle. In such a device11 the intermediate capsule 14 may be coated at 18 to prevent immediaterelease, as may the inner capsule 16 at 19, the effect being a“three-pulse” system in which the active principle 13, 15, 17 isdelivered, or at least made available, in a controlled fashion.Moreover, with a surreptitious choice of coatings 18, 19, a so-called“parallel” device 21 as shown in FIG. 3 could also be used.

FIG. 4C shows a composite pharmaco-kinetic profile Y in which sustainedrelease of the active principle is described. The delivery devices 11,21 may be arranged to provide such a profile Y. In some cases, a largedose of a principle is required although the body may not respondpositively to a large immediate dose. Thus the active principleconcentration is “ramped-up” slowly by sequential release of activeprinciple from sequential breakdown of the capsules. In FIG. 4C, threereleases R₂₁, R₂₂, R₂₃ are indicated. With certain medicaments, thetoxicity threshold To may increase once the body has adjusted to theinitial dose. In such circumstances, it is beneficial to providesequential release of the active principle, taking advantage of thepatient's increased tolerance thereof.

FIG. 4D shows a representation of a further composite pharmaco-kineticprofile Z in which two releases R₃₁, R₃₂ are indicated. The firstrelease R₃₁ shows a rapid rise in active principle concentration whichequally rapidly dies away, the second release R₃₂ providing a sustainedrelease of active principle. This matched acute and chronic releaseprofile provides a composite pharmaco-kinetic profile Z in which thepatient is exposed to a large initial concentration of active principlefollowed by a sustained increase in active principle concentration. Sucha profile Z may be desirable in circumstance where the initial doseprimes the patient for a more sustained dose. Both serial and paralleldevices 1, 11, 21 may be utilised to provide such a profile, withcareful consideration being given to the choice of coatings 6, 18, 19which could be applied to any or all of the capsules 2, 4; 12, 14, 16;22, 24.

The FIGS. 4A to 4D show particular pharmaco-kinetic profiles W, X, Y andZ. It will be understood by the skilled addressee that many desiredprofiles are achievable. For example, it is a simple matter to provide,or at least closely approximate, a steady-state active principleconcentration, which is to say an invariant pharmaco-kinetic profileover time, the rate of removal being equal to the rate ofrelease/absorption of active principle. In such a fashion, thegastrointestinal (GI) tract, or at least a portion thereof, may besubjected to an at least approximately constant concentration of activeprinciple as a delivery, device 1, 11, 21 travels therealong, releasingits active principle. Alternatively, a certain portion of the GI tractmay be subjected to a steady-state concentration whilst another portionis subjected to a pulse of active principle, for example.

The above discussion has been silent as to the most efficacious site ofprinciple delivery. The delivery devices 1, 11, 21 can be used todeliver their contents to the most efficacious site in thegastrointestinal (GI) tract. For example, certain active principles maynot be best suited for uptake from the acidic conditions prevalent inthe stomach and may be best suited for up-take in the colon. In suchcircumstance the capsules can be coated such that they are only slowlydissolved under strongly acidic conditions, thereby bypassing thestomach.

Moreover, it may be desirable to deliver an active principle to morethan one site in the GI tract, for example the stomach and the colon.For such a delivery regime, the inner capsule 4 may be provided with acoating which slowly dissolves once exposed to the conditions of thestomach, the outer capsule 2 having been dissolved soon after ingestion.In this case, the coating is arranged to dissolve, under the prevailingconditions, in the time taken for the device 1 to travel from thestomach to the desired delivery site. A typical release profile may beshown by the pharmaco-kinetic profile Z of FIG. 4D in which the firstrelease R₃₁ occurs in the stomach and the second release R₃₂ occursfurther down the GI tract, for example in the colon. As is shown, theactive principle concentration in the stomach and colon of the activeprinciple are distinct due to the differing environmental conditions,the desired treatment regime and the efficacy of the active principle ineach location.

An example of the potential uses of such a regime is in the treatment ofexcess dissolved intestinal gases. Intestinal wind is, in the main,caused by the swallowing of air whilst eating and drinking together withthe small amount which is formed through the bi-products of bacterialdigestion within the stomach and GI tract. These gases become dissolvedin the stomach contents and can cause discomfort, in some cases pain,and embarrassment. The usual way to treat such an ailment is to providemedicaments such as simethicone or dimethicone which reduce the surfacetension of the stomach GI tract contents, allowing the dissolved gasesto come out of solution and be released from the body. Whilst theproblem of dissolved gases can be addressed in the stomach it isconventionally relatively difficult to treat the problem lower in the GItract without using high doses. The delivery device 1 may be used to doso, in the manner discussed above with a lower dose of the activeprinciple.

A further method of altering the release rate, and thus the absorbanceprofile, of an active principle, is to provide the same active principlein a two or more different and distinct phases, for example solid andliquid within a single capsule. For example, the delivery device 1 ofFIG. 1 may comprise an uncoated outer capsule 2 in which is situated aliquid active principle 3 and a coated inner capsule 4. The innercapsule 4 may contain the same active principle 5 in, for example, anaqueous liquid formulation and a coated solid, such as pellet,formulation. The encapsulated active principle could also bethermosoftening, which is to say that as the temperature increases theviscosity of the active principle decreases.

Once the outer capsule 2 has dissolved and the contents 3 thereof havebeen absorbed, the inner capsule 4 starts to dissolve. Once this hasoccurred the aqueous liquid formulation of the active principle 5 israpidly absorbed whilst the coating on the pellets is dissolving. Asthat coating dissolves, the solid formulation of the active principle isabsorbed by the patient providing a double pulse and sustained releasecomposite pharmaco-kinetic profile.

Such delivery devices 1; 11; 21 may also be used to separate immisciblecomponents. For example, in certain therapies it is beneficial todeliver the same active principle in a variety of solvents. Suchsolvents may be water and lipids or fats, the inner capsule 4containing, for example, an aqueous liquid formulation of the activeprinciple 5 and the outer capsule 2 containing a lipidic formulation ofthe same active principle 3. These same principles 3, 5 may be deliveredto the same or different sites within the body as the treatmentnecessitates and which delivery sites may be controlled by a coating onthe capsules 2, 4.

Thus, it can be seen that with an adroit choice of coating and/or byconsideration of the capsules dissolution profile, which is to say therate at which the capsule dissolves, the delivery device 1; 11; 21 canbe arranged to provide the desired pharmaco-kinetic profile fortreatment of a particular ailment. This can also be augmented by theprovision of the same active principle in a particular phase or inparticular phases within each capsule. The provision of serial andparallel arrangements of capsules within a delivery device may also beutilised to control or vary the release of active principle.

In further embodiments, the delivery device, for example 1, may comprisefurther active principles together with the same primary principle. Forexample, the outer capsule 2 may contain a main active principle 3together with another, second active principle, whereas inner capsule 4may contain the same main active principle 5 and a further, third activeprinciple, main principles 3 and 5 being the same in the same ordifferent phases. The above-identified second and third activeprinciples may inhibit each others activity or it may be desirable totreat a different site within the GI tract with each or they may actsynergistically in an undesired fashion. The delivery device 1 affords aclinician the ability to provide all three principles in one deliverydevice, whilst pre-determining the active principle release profiles andthe site of release. This leads to directed treatment of one or morespecific ailments, allowing medical staff to accurately target deliverysites and ensure that the active principle concentration is optimum.

It is known that different shell materials exhibit a wide-range ofproperties. For example, gelatin capsules show an excellent resistanceto oxygen penetration but are readily embrittled by the loss of moisturetherefrom. However, HPMC capsules are readily penetrated by oxygenwhilst being very resistant to moisture embrittlement. Therefore, anoxygen sensitive active principle could be encapsulated within an innergelatin capsule 4 which is in turn encapsulated within an outer HPMCcapsule 2 containing, for example, a non oxygen sensitive formulation.The HPMC outer capsule 2 provides a flexible tough outer shell whilstthe brittle inner gelatin capsule 4, which is protected by support fromthe surrounding active principle, provides protection against oxidationof its contents.

It has been demonstrated that the delivery devices 1; 11; 21 allow for aflexibility of delivery of an active principle. By a simple choice ofcapsule materials, together with manipulation of capsule coating and orformulation of the active principle it is possible to accurately andprecisely target active principle delivery site and concentration. Italso allows for incompatible substances to be separated until such timesas they are released or, indeed, to keep substances completelyseparated, delivering said principles to distinct sites.

Moreover, it allows for the simplification of a treatment regime. Thedelivery devices 1; 11; 21 provide means for controlling complicatedtreatment regimes and removing some or all of the onus from the patient.In some therapies, cocktails of drugs are prescribed which have to betaken at set times, after meals for example, or in pre-determinedpatterns. Use of the inventive delivery devices 1; 11; 21 allows fordrastic simplification of that procedure which may have profound effectsin, for example, rural locations of developing countries where literacyrates may be low and clinicians are not on hand to supervise everyaspect of a patient's treatment.

Moreover, in the treatment of animals such simplification ofadministration regimes is desired. For example, it may be difficult orarduous to repetitively administer medicaments to animals to treat aparticular complaint. The inventive delivery devices 1; 11; 21 providemeans to simplify that procedure, ensuring that the animal receives thedesired dose of medicament whilst minimising the number of times a vet,for example, has to visit the animal and simplifying the treatmentregime.

In, certain medical or other uses, time and one or more prevailingenvironmental conditions may affect the release rate. For example, theacidity of the stomach may partially control the release rate.

It is clear, therefore, that the inventive delivery devices 1; 11; 21and associated methods provide means of delivering active principles andother components to a desired site by control of a few simpleparameters. It should be understood that although the invention has beendescribed with reference to the above examples, the ambit of theinvention is to be determined by the appended claims.

It is to be appreciated that certain features of the invention, whichare, for clarity, described in the context of separate embodiments, mayalso be provided in combination in a single embodiment. Conversely,various features of the invention which are, for brevity, described inthe context of a single embodiment, may also be provided separately orin any suitable sub-combination.

1. An active principle delivery device for controlling a release rateand delivery site of a medicinal and/or nutritional active principle,the delivery device being formed from fillable outer and inner capsules,the outer capsule containing the active principle, the inner capsulewithin the outer capsule also containing the active principle, at leastthe outer capsule being a hard capsule, and the active principle in atleast the outer capsule comprising a fluid; wherein the active principlecontained by at least the outer capsule is a liquid either at orimmediately prior to its time of use or during its manufacture; whereinthe liquid comprises a solution and/or a suspension of the activeprinciple; and wherein the liquid is thermosoftening.
 2. An activeprinciple delivery device for controlling a release rate and deliverysite of a medicinal and/or nutritional active principle, the deliverydevice being formed from fillable outer and inner capsules, the outercapsule containing the active principle, the inner capsule within theouter capsule also containing the active principle, at least the outercapsule being a hard capsule, and the active principle in at least theouter capsule comprising a fluid; wherein at least the outer capsuleconsists of a material selected from the group consisting of gelatin,plasticised gelatin, hydroxy propyl methyl cellulose, starch, and agar.3. An active principle delivery device for controlling a release rateand delivery site of a medicinal and/or nutritional active principle,the delivery device being formed from fillable outer and inner capsules,the outer capsule containing the active principle, the inner capsulewithin the outer capsule also containing the active principle, at leastthe outer capsule being a hard capsule, and the active principle in atleast the outer capsule comprising a fluid; wherein at least one of theinner and outer capsules is coated or uncoated in accordance with adesired release profile of the active principle.
 4. An active principledelivery device for controlling a release rate and delivery site of amedicinal and/or nutritional active principle, the delivery device beingformed from fillable outer and inner capsules, the outer capsulecontaining the active principle, the inner capsule within the outercapsule also containing the active principle, at least the outer capsulebeing a hard capsule, and the active principle in at least the outercapsule comprising a fluid; wherein the active principle comprises afluid-suspended solid.
 5. A delivery device according to claim 4,wherein the fluid-suspended solid consists of a member selected from thegroup consisting of a powder, a pellet, and granules.
 6. A deliverydevice according to claim 4, wherein the fluid-suspended solid is coatedor uncoated in accordance with a desired release profile of the activeprinciple.
 7. A delivery device according to claim 5, wherein thefluid-suspended solid is coated or uncoated in accordance with a desiredrelease profile of the active principle.
 8. An active principle deliverydevice for controlling a release rate and delivery site of a medicinaland/or nutritional active principle, the delivery device being formedfrom fillable outer and inner capsules, the outer capsule containing theactive principle, the inner capsule within the outer capsule alsocontaining the active principle, at least the outer capsule being a hardcapsule, and the active principle in at least the outer capsulecomprising a fluid; wherein at least one of the inner and outer capsulescontains the active principle in more than one phase.
 9. An activeprinciple delivery device for controlling a release rate and deliverysite of a medicinal and/or nutritional active principle, the deliverydevice being formed from fillable outer and inner capsules, the outercapsule containing the active principle, the inner capsule within theouter capsule also containing the active principle, at least the outercapsule being a hard capsule, and the active principle in at least theouter capsule comprising a fluid, the delivery device comprising morethan one inner capsule within the outer capsule, the inner capsulesbeing arranged in parallel with each other.
 10. An active principledelivery device for controlling a release rate and delivery site of amedicinal and/or nutritional active principle, the delivery device beingformed from fillable outer and inner capsules, the outer capsulecontaining the active principle, the inner capsule within the outercapsule also containing the active principle, at least the outer capsulebeing a hard capsule, and the active principle in at least the outercapsule comprising a fluid, the delivery device comprising more than oneinner capsule within the outer capsule, the inner capsule being arrangedin series with each other.
 11. An active principle delivery device forcontrolling a release rate and delivery site of a medicinal and/ornutritional active principle, the delivery device being formed fromfillable outer and inner capsules, the outer capsule containing theactive principle, the inner capsule within the outer capsule alsocontaining the active principle, at least the outer capsule being a hardcapsule, and the active principle in at least the outer capsulecomprising a fluid, the delivery device further comprising an activatoror co-reactant for the active principle.
 12. A method of fabricating anactive principle delivery device, the method comprising the steps of:providing fillable first and second capsules of which at least the firstcapsule is a hard capsule; placing an identical active principle in eachof the first and second capsules, with the active principle in at leastthe outer capsule comprising a fluid; and placing the second capsulewithin the first capsule; wherein at least the first capsule consists ofa material selected from the group consisting of gelatin, plasticizedgelatin, hydroxy propyl methyl cellulose, starch, and agar.
 13. A methodof fabricating an active principle delivery device, the methodcomprising the steps of: providing fillable first and second capsules ofwhich at least the first capsule is a hard capsule; placing an identicalactive principle in each of the first and second capsules, with theactive principle in at least the outer capsule comprising a fluid; andplacing the second capsule within the first capsule; wherein at leastone of the first and second capsules is coated or uncoated in accordancewith a desired release profile of the active principle.
 14. A method offabricating an active principle delivery device, the method comprisingthe steps of: providing fillable first and second capsules of which atleast the first capsule is a hard capsule; placing an identical activeprinciple in each of the first and second capsules, with the activeprinciple in at least the outer capsule comprising a fluid; and placingthe second capsule within the first capsule; wherein the liquid isthermosoftening and comprises a solution and/or a suspension of theactive principle.
 15. A method of fabricating an active principledelivery device, the method comprising the steps of: providing fillablefirst and second capsules of which at least the first capsule is a hardcapsule; placing an identical active principle in each of the first andsecond capsules, with the active principle in at least the outer capsulecomprising a fluid; and placing the second capsule within the firstcapsule; wherein the active principle comprises a fluid-suspended solid.16. A method according to claim 15, wherein the fluid-suspended solidconsists of a member selected from the group consisting of a powder, apellet, and granules.
 17. A method according to claim 15, furthercomprising the step of formulating a desired release profile of theactive principle and providing the suspended solid in coated or uncoatedform, such that the release thereof accords with the desired releaseprofile.
 18. A method according to claim 16, further comprising the stepof formulating a desired release profile of the active principle andproviding the suspended solid in coated or uncoated form, such that therelease thereof accords with the desired release profile.
 19. A methodaccording to claim 17, wherein the desired release profile is determinedby a nominal or theoretical pharmaco-kinetic profile of the activeprinciple.
 20. A method according to claim 18, wherein the desiredrelease profile is determined by a nominal or theoreticalpharmaco-kinetic profile of the active principle.
 21. A method offabricating an active principle delivery device, the method comprisingthe steps of: providing fillable first and second capsules of which atleast the first capsule is a hard capsule; placing an identical activeprinciple in each of the first and second capsules, with the activeprinciple in at least the outer capsule comprising a fluid; and placingthe second capsule within the first capsule; wherein at least one of thefirst and second capsules contains the active principle in more than onephase.
 22. A method of fabricating an active principle delivery device,the method comprising the steps of: providing fillable first and secondcapsules of which at least the first capsule is a hard capsule; placingan identical active principle in each of the first and second capsules,with the active principle in at least the outer capsule comprising afluid; and placing the second capsule within the first capsule; whereinmore than one second capsule is placed within the first capsule, thesecond capsules being arranged in parallel with each other.
 23. A methodof fabricating an active principle delivery device, the methodcomprising the steps of: providing fillable first and second capsules ofwhich at least the first capsule is a hard capsule; placing an identicalactive principle in each of the first and second capsules, with theactive principle in at least the outer capsule comprising a fluid; andplacing the second capsule within the first capsule; wherein more thanone second capsule is placed within the first capsule, the secondcapsules being arranged in series with each other.
 24. A method offabricating an active principle delivery device, the method comprisingthe steps of: providing fillable first and second capsules of which atleast the first capsule is a hard capsule; placing an identical activeprinciple in each of the first and second capsules, with the activeprinciple in at least the outer capsule comprising a fluid; and placingthe second capsule within the first capsule; further comprising the stepof providing an activator or co-reactant for the active principle withinthe delivery device.
 25. A method of controlling the pharmaco-kineticprofile of an active principle, the method comprising the steps of:determining a first efficacious site for active principle release;placing an active principle in a first hard fillable capsule; placingthe same active principle in a second fillable capsule within the firsthard fillable capsule, with the active principle in at least the firsthard fillable capsule comprising a fluid; delivering the delivery deviceto the predetermined site; and controlling the release of the activeprinciple at the site.
 26. A method according to claim 25, furthercomprising the steps of: determining a second efficacious site for theactive principle release; delivering at least a portion of the deliverydevice to the second site subsequent to the delivery of the device tothe first site; and controlling the release of the active principle atthe second site.
 27. A method according to claim 25, wherein the activeprinciple comprises a medicinal or nutritional product.
 28. A methodaccording to claim 25, wherein the control of the release of the activeprinciple is afforded by the dissolution characteristics of at least oneof the first hard fillable capsule and the second fillable capsule.